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HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells

Oncogene volume 25, pages 1721–1732 (2006)Cite this article

A Corrigendum to this article was published on 08 November 2007

Abstract

The highly invasive behavior of glioblastoma cells contributes to the morbidity and mortality associated with these tumors. The integrin-mediated adhesion and migration of glioblastoma cells on brain matrix proteins is enhanced by stimulation with growth factors, including platelet-derived growth factor (PDGF). As focal adhesion kinase (FAK), a nonreceptor cytoplasmic tyrosine kinase, has been shown to promote cell migration in various other cell types, we analysed its role in glioblastoma cell migration. Forced overexpression of FAK in serum-starved glioblastoma cells plated on recombinant (rec)-osteopontin resulted in a twofold enhancement of basal migration and a ninefold enhancement of PDGF-BB-stimulated migration. Both expression of mutant FAK(397F) and the downregulation of FAK with small interfering (si) RNA inhibited basal and PDGF-stimulated migration. FAK overexpression and PDGF stimulation was found to increase the phosphorylation of the Crk-associated substrate (CAS) family member human enhancer of filamentation 1 (HEF1), but not p130CAS or Src-interacting protein (Sin)/Efs, although the levels of expression of these proteins was similar. Moreover downregulation of HEF1 with siRNA, but not p130CAS, inhibited basal and PDGF-stimulated migration. The phosphorylated HEF1 colocalized with vinculin and was associated almost exclusively with 0.1% Triton X-100 insoluble material, consistent with its signaling at focal adhesions. FAK overexpression promoted invasion through normal brain homogenate and siHEF1 inhibited this invasion. Results presented here suggest that HEF1 acts as a necessary and specific downstream effector of FAK in the invasive behavior of glioblastoma cells and may be an effective target for treatment of these tumors.

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Abbreviations

CAS:

crk-associated substrate

Efs:

embryonic Fyn substrate

EGF:

epidermal growth factor

EGFR:

EGF receptor

FAK:

focal adhesion kinase

HEF1:

human enhancer of filamentation 1

IP:

immunoprecipitation

PDGF:

platelet-derived growth factor BB

PDGFr:

PDGF receptor

rec:

recombinant

si:

small interfering

Sin:

Src-interacting protein

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Acknowledgements

We thank Mrs Jo Self for preparation of the manuscript. This work was supported by Grants CA97110, CA97247 (Proj. 5), and CA109748 from the National Institutes of Health, National Cancer Institute to CLG.

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Authors and Affiliations

  1. Department of Pathology, Division of Neuropathology, University of Alabama at Birmingham, AL, USA

    M Natarajan, J E Stewart Jr, B D Cox, J R Grammer & C L Gladson

  2. Division of Basic Sciences, Fox Chase Cancer Center, Philadelphia, PA, USA

    E A Golemis & E N Pugacheva

  3. Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY, USA

    K Alexandropoulos

  4. Department of Medicine, Division of Hematology–Oncology (Biostatistics Section), University of Alabama at Birmingham, AL, USA

    W Wang

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  1. M Natarajan
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Correspondence to C L Gladson.

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Natarajan, M., Stewart, J., Golemis, E. et al. HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells. Oncogene 25, 1721–1732 (2006). https://doi.org/10.1038/sj.onc.1209199

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